As a consequence of the environmental pollution due to the intensive industrialization and the consumption many poisonous compounds can accumulate in the human body and in the environment. From these compounds the most important ones are the lead (Pb) and the mercury (Hg) which can accumulate in the fatty tissue and cause severe acute or fatal poisoning. Radioactive strontium (Sr) and caesium (Cs) releasing to the environment as a consequence of nuclear catastrophes (Three-miles Island, N.Y. 1979; Chernobyl, USSR: 1986; Fukusima, Japan: 2011, Csillebérc, Hungary: 2011) and causing environmental, health and social damages accumulate in the bones and result in long-lasting poisoning.
For the removal of the above-mentioned poisoning compounds so called “chelate-forming” compounds can be used which remove the toxic metals from the body.
In the most cases these compounds have no specific effect. For example, in the case of ethylene-diamine-tetraacetic acid (EDTA) or diethylene-triamine-pentaacetic acid the calcium complexes are more stable than the strontium complexes, as described in lines 15-18 of the first paragraph on page 3 of the Hungarian Patent No. 209389. Since these complexes are not specific, during the use of them essential metals (such as Ca and Mg) can also be removed. Therefore in the Hungarian Patent No. 209386 more specific macrocyclic compounds, so called “criptand” derivatives were suggested for the removal of the strontium from the body. The parameters of the molecular structure of the macrocyclic compounds define which ion is bound to the compounds the strongest, thus for the specific removal of the different toxic metal ions complex-forming compounds are necessary, which bind the toxic metal ions significantly better.
The Hungarian Patent No. 209386 discloses such complex-forming agents which are based on a Kriptofix compound binding the strontium selectively. One member of these compounds is the compound of the formula
(7,16-bis-malonate)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-bis-malonic acid, which was prepared in Ca complex form as well. The compound of the formula (XI) verified a stronger activity with strontium than calcium in physico-chemical and in vivo experiments on mice. In the in vivo experiments the strontium administered artificially in a different amount could be removed selectively by the compound of the formula (XI) added intravenously, thus preventing its accumulation in the bones, while the calcium remained.
Furthermore, in vitro experiments show affinity with other toxic metal ions, which strengthens the usability of this compound. The efficacy of this compound is shown in examples 18 and 19 of the Hungarian Patent 209386. In these examples a salt of the compound of the formula (XI) is added intravenously into the body of rats in an amount of 50-100 micromoles/body weight kilogram. Taking into consideration that the molecular weight of the complexes and salts of the compound of the formula (XI) is 550-650, the single dose having an excellent effect for an adult human patient (70 body weight kg) can be even 4-4.5 g. According to the last line of the second column on page 3, and in lines 1-2 of the first column on page 4 of the description of the Hungarian Patent No. 209389 the salts of the compound of (XI) were administered intravenously in a concentration of 100-500 mg/l in animal experiments. A further disadvantage of the compound of the formula (XI) is that the malonic acid sub-structure decarboxylates easily and the strontium complex of the resulted compound is not soluble and precipitates from the aqueous medium, which can prevent the excretion of the strontium ion from the body. In course of another decomposition of the compound malonic acid cleaves from the compound which is a strong cytotoxin. The reason for this feature is that its structure is similar to that of the succinic acid which has a key role in the cellular respiration and therefore inhibits the function of succinate dehydrogenase enzyme. The tendency of decarboxylation can increase in the presence of other heavy metals having Lewis acidic properties such as lead (Pb) or tin (Sn), which is proved by our experimental results measured with mass spectrometer. The decarboxylation also reduces the complex-forming effect.
Therefore an idea has arisen to prepare complex-forming agents, the selectivity of which is similar to the compound of the formula (XI), but more effective, more water soluble, and do not transform to toxic compounds in course of their incidental metabolism in the body and are stable during storage. These compounds would allow the reduction of the amount of used dose. Since these compounds are usually used in catastrophes, they have to be stored in a large amount and for a long time.
The mere fact that compounds have 1.5-2 fold more effective complex-forming compounds than the known ones, reduces significantly the expenses of the preparation for catastrophes. On the other hand it is also important that the complex-forming compounds do not bind significantly and do not remove the microelements from the body which are important for the living beings such as zinc and copper.